Use of a vegf antagonist to treat angiogenic eye disorders

ABSTRACT

The present invention provides methods for treating angiogenic eye disorders by sequentially administering multiple doses of a VEGF antagonist to a patient. The methods of the present invention include the administration of multiple doses of a VEGF antagonist to a patient at a frequency of once every 8 or more weeks. The methods of the present invention are useful for the treatment of angiogenic eye disorders such as age related macular degeneration, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, and corneal neovascularization.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International PatentApplication No. PCT/US2012/020855, filed on Jan. 11, 2012, which claimsthe benefit of U.S. Provisional Application No. 61/432,245, filed onJan. 13, 2011, 61/434,836, filed on Jan. 21, 2011, and 61/561,957, filedon Nov. 21, 2011, the contents of which are hereby incorporated byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to the field of therapeutic treatments ofeye disorders. More specifically, the invention relates to theadministration of VEGF antagonists to treat eye disorders caused by orassociated with angiogenesis.

BACKGROUND

Several eye disorders are associated with pathological angiogenesis. Forexample, the development of age-related macular degeneration (AMD) isassociated with a process called choroidal neovascularization (CNV).Leakage from the CNV causes macular edema and collection of fluidbeneath the macula resulting in vision loss. Diabetic macular edema(DME) is another eye disorder with an angiogenic component. DME is themost prevalent cause of moderate vision loss in patients with diabetesand is a common complication of diabetic retinopathy, a diseaseaffecting the blood vessels of the retina. Clinically significant DMEoccurs when fluid leaks into the center of the macula, thelight-sensitive part of the retina responsible for sharp, direct vision.Fluid in the macula can cause severe vision loss or blindness. Yetanother eye disorder associated with abnormal angiogenesis is centralretinal vein occlusion (CRVO). CRVO is caused by obstruction of thecentral retinal vein that leads to a back-up of blood and fluid in theretina. The retina can also become ischemic, resulting in the growth ofnew, inappropriate blood vessels that can cause further vision loss andmore serious complications. Release of vascular endothelial growthfactor (VEGF) contributes to increased vascular permeability in the eyeand inappropriate new vessel growth. Thus, inhibiting theangiogenic-promoting properties of VEGF appears to be an effectivestrategy for treating angiogenic eye disorders.

FDA-approved treatments of angiogenic eye disorders such as AMD and CRVOinclude the administration of an anti-VEGF antibody called ranibizumab(Lucentis®, Genentech, Inc.) on a monthly basis by intravitrealinjection.

Methods for treating eye disorders using VEGF antagonists are mentionedin, e.g., U.S. Pat. No. 7,303,746; U.S. Pat. No. 7,306,799; U.S. Pat.No. 7,300,563; U.S. Pat. No. 7,303,748; and US 2007/0190058.Nonetheless, there remains a need in the art for new administrationregimens for angiogenic eye disorders, especially those which allow forless frequent dosing while maintaining a high level of efficacy.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods for treating angiogenic eyedisorders. The methods of the invention comprise sequentiallyadministering multiple doses of a VEGF antagonist to a patient overtime. In particular, the methods of the invention comprise sequentiallyadministering to the patient a single initial dose of a VEGF antagonist,followed by one or more secondary doses of the VEGF antagonist, followedby one or more tertiary doses of the VEGF antagonists. The presentinventors have surprisingly discovered that beneficial therapeuticeffects can be achieved in patients suffering from angiogenic eyedisorders by administering a VEGF antagonist to a patient at a frequencyof once every 8 or more weeks, especially when such doses are precededby about three doses administered to the patient at a frequency of about2 to 4 weeks. Thus, according to the methods of the present invention,each secondary dose of VEGF antagonist is administered 2 to 4 weeksafter the immediately preceding dose, and each tertiary dose isadministered at least 8 weeks after the immediately preceding dose. Anexample of a dosing regimen of the present invention is shown in FIG. 1.One advantage of such a dosing regimen is that, for most of the courseof treatment (i.e., the tertiary doses), it allows for less frequentdosing (e.g., once every 8 weeks) compared to prior administrationregimens for angiogenic eye disorders which require monthlyadministrations throughout the entire course of treatment. (See, e.g.,prescribing information for Lucentis® [ranibizumab], Genentech, Inc.).

The methods of the present invention can be used to treat any angiogeniceye disorder, including, e.g., age related macular degeneration,diabetic retinopathy, diabetic macular edema, central retinal veinocclusion, corneal neovascularization, etc.

The methods of the present invention comprise administering any VEGFantagonist to the patient. In one embodiment, the VEGF antagonistcomprises one or more VEGF receptor-based chimeric molecule(s), (alsoreferred to herein as a “VEGF-Trap” or “VEGFT”). An exemplary VEGFantagonist that can be used in the context of the present invention is amultimeric VEGF-binding protein comprising two or more VEGFreceptor-based chimeric molecules referred to herein as“VEGFR1R2-FcΔC1(a)” or “aflibercept.”

Various administration routes are contemplated for use in the methods ofthe present invention, including, e.g., topical administration orintraocular administration (e.g., intravitreal administration).

Aflibercept (EYLEA™, Regeneron Pharmaceuticals, Inc) was approved by theFDA in November 2011, for the treatment of patients with neovascular(wet) age-related macular degeneration, with a recommended dose of 2 mgadministered by intravitreal injection every 4 weeks for the first threemonths, followed by 2 mg administered by intravitreal injection onceevery 8 weeks.

Other embodiments of the present invention will become apparent from areview of the ensuing detailed description.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows an exemplary dosing regimen of the present invention. Inthis regimen, a single “initial dose” of VEGF antagonist (“VEGFT”) isadministered at the beginning of the treatment regimen (i.e. at “week0”), two “secondary doses” are administered at weeks 4 and 8,respectively, and at least six “tertiary doses” are administered onceevery 8 weeks thereafter, i.e., at weeks 16, 24, 32, 40, 48, 56, etc.).

DETAILED DESCRIPTION

Before the present invention is described, it is to be understood thatthis invention is not limited to particular methods and experimentalconditions described, as such methods and conditions may vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting, since the scope of the present invention will be limitedonly by the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. As used herein, the term“about,” when used in reference to a particular recited numerical value,means that the value may vary from the recited value by no more than 1%.For example, as used herein, the expression “about 100” includes 99 and101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention, the preferred methods and materials are now described.

Dosing Regimens

The present invention provides methods for treating angiogenic eyedisorders. The methods of the invention comprise sequentiallyadministering to a patient multiple doses of a VEGF antagonist. As usedherein, “sequentially administering” means that each dose of VEGFantagonist is administered to the patient at a different point in time,e.g., on different days separated by a predetermined interval (e.g.,hours, days, weeks or months). The present invention includes methodswhich comprise sequentially administering to the patient a singleinitial dose of a VEGF antagonist, followed by one or more secondarydoses of the VEGF antagonist, followed by one or more tertiary doses ofthe VEGF antagonist.

The terms “initial dose,” “secondary doses,” and “tertiary doses,” referto the temporal sequence of administration of the VEGF antagonist. Thus,the “initial dose” is the dose which is administered at the beginning ofthe treatment regimen (also referred to as the “baseline dose”); the“secondary doses” are the doses which are administered after the initialdose; and the “tertiary doses” are the doses which are administeredafter the secondary doses. The initial, secondary, and tertiary dosesmay all contain the same amount of VEGF antagonist, but will generallydiffer from one another in terms of frequency of administration. Incertain embodiments, however, the amount of VEGF antagonist contained inthe initial, secondary and/or tertiary doses will vary from one another(e.g., adjusted up or down as appropriate) during the course oftreatment.

In one exemplary embodiment of the present invention, each secondarydose is administered 2 to 4 (e.g., 2, 2½, 3, 3½, or 4) weeks after theimmediately preceding dose, and each tertiary dose is administered atleast 8 (e.g., 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14,14½, or more) weeks after the immediately preceding dose. The phrase“the immediately preceding dose,” as used herein, means, in a sequenceof multiple administrations, the dose of VEGF antagonist which isadministered to a patient prior to the administration of the very nextdose in the sequence with no intervening doses.

In one exemplary embodiment of the present invention, a single initialdose of a VEGF antagonist is administered to a patient on the first dayof the treatment regimen (i.e., at week 0), followed by two secondarydoses, each administered four weeks after the immediately preceding dose(i.e., at week 4 and at week 8), followed by at least 5 tertiary doses,each administered eight weeks after the immediately preceding dose(i.e., at weeks 16, 24, 32, 40 and 48). The tertiary doses may continue(at intervals of 8 or more weeks) indefinitely during the course of thetreatment regimen. This exemplary administration regimen is depictedgraphically in FIG. 1.

The methods of the invention may comprise administering to a patient anynumber of secondary and/or tertiary doses of a VEGF antagonist. Forexample, in certain embodiments, only a single secondary dose isadministered to the patient. In other embodiments, two or more (e.g., 2,3, 4, 5, 6, 7, 8, or more) secondary doses are administered to thepatient. Likewise, in certain embodiments, only a single tertiary doseis administered to the patient. In other embodiments, two or more (e.g.,2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to thepatient.

In embodiments involving multiple secondary doses, each secondary dosemay be administered at the same frequency as the other secondary doses.For example, each secondary dose may be administered to the patient 4weeks after the immediately preceding dose. Similarly, in embodimentsinvolving multiple tertiary doses, each tertiary dose may beadministered at the same frequency as the other tertiary doses. Forexample, each tertiary dose may be administered to the patient 8 weeksafter the immediately preceding dose. Alternatively, the frequency atwhich the secondary and/or tertiary doses are administered to a patientcan vary over the course of the treatment regimen. For example, thepresent invention includes methods which comprise administering to thepatient a single initial dose of a VEGF antagonist, followed by one ormore secondary doses of the VEGF antagonist, followed by at least 5tertiary doses of the VEGF antagonist, wherein the first four tertiarydoses are administered 8 weeks after the immediately preceding dose, andwherein each subsequent tertiary dose is administered from 8 to 12(e.g., 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12) weeks after the immediatelypreceding dose. The frequency of administration may also be adjustedduring the course of treatment by a physician depending on the needs ofthe individual patient following clinical examination.

VEGF Antagonists

The methods of the present invention comprise administering to a patienta VEGF antagonist according to specified dosing regimens. As usedherein, the expression “VEGF antagonist” means any molecule that blocks,reduces or interferes with the normal biological activity of VEGF.

VEGF antagonists include molecules which interfere with the interactionbetween VEGF and a natural VEGF receptor, e.g., molecules which bind toVEGF or a VEGF receptor and prevent or otherwise hinder the interactionbetween VEGF and a VEGF receptor. Specific exemplary VEGF antagonistsinclude anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGFreceptor-based chimeric molecules (also referred to herein as“VEGF-Traps”).

VEGF receptor-based chimeric molecules include chimeric polypeptideswhich comprise two or more immunoglobulin (Ig)-like domains of a VEGFreceptor such as VEGFR1 (also referred to as Flt1) and/or VEGFR2 (alsoreferred to as Flk1 or KDR), and may also contain a multimerizing domain(e.g., an Fc domain which facilitates the multimerization [e.g.,dimerization] of two or more chimeric polypeptides). An exemplary VEGFreceptor-based chimeric molecule is a molecule referred to asVEGFR1R2-FcΔC1(a) which is encoded by the nucleic acid sequence of SEQID NO:1. VEGFR1R2-FcΔC1(a) comprises three components: (1) a VEGFR1component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2component comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) amultimerization component (“FcΔC1(a)”) comprising amino acids 232 to 457of SEQ ID NO:2 (the C-terminal amino acid of SEQ ID NO:2 [i.e., K458]may or may not be included in the VEGF antagonist used in the methods ofthe invention; see e.g., U.S. Pat. No. 7,396,664). Amino acids 1-26 ofSEQ ID NO:2 are the signal sequence.

The VEGF antagonist used in the Examples set forth herein below is adimeric molecule comprising two VEGFR1R2-FcΔC1(a) molecules and isreferred to herein as “VEGFT.” Additional VEGF receptor-based chimericmolecules which can be used in the context of the present invention aredisclosed in U.S. Pat. Nos. 7,396,664, 7,303,746 and WO 00/75319.

Angiogenic Eye Disorders

The methods of the present invention can be used to treat any angiogeniceye disorder. The expression “angiogenic eye disorder,” as used herein,means any disease of the eye which is caused by or associated with thegrowth or proliferation of blood vessels or by blood vessel leakage.Non-limiting examples of angiogenic eye disorders that are treatableusing the methods of the present invention include age-related maculardegeneration (e.g., wet AMD, exudative AMD, etc.), retinal veinocclusion (RVO), central retinal vein occlusion (CRVO; e.g., macularedema following CRVO), branch retinal vein occlusion (BRVO), diabeticmacular edema (DME), choroidal neovascularization (CNV; e.g., myopicCNV), iris neovascularization, neovascular glaucoma, post-surgicalfibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic discneovascularization, corneal neovascularization, retinalneovascularization, vitreal neovascularization, pannus, pterygium,vascular retinopathy, and diabetic retinopathies.

Pharmaceutical Formulations

The present invention includes methods in which the VEGF antagonist thatis administered to the patient is contained within a pharmaceuticalformulation. The pharmaceutical formulation may comprise the VEGFantagonist along with at least one inactive ingredient such as, e.g., apharmaceutically acceptable carrier. Other agents may be incorporatedinto the pharmaceutical composition to provide improved transfer,delivery, tolerance, and the like. The term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly, inhumans. The term “carrier” refers to a diluent, adjuvant, excipient, orvehicle with which the antibody is administered. A multitude ofappropriate formulations can be found in the formulary known to allpharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed,Mack Publishing Company, Easton, Pa., 1975), particularly Chapter 87 byBlaug, Seymour, therein. These formulations include, for example,powders, pastes, ointments, jellies, waxes, oils, lipids, lipid(cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNAconjugates, anhydrous absorption pastes, oil-in-water and water-in-oilemulsions, emulsions carbowax (polyethylene glycols of various molecularweights), semi-solid gels, and semi-solid mixtures containing carbowax.Any of the foregoing mixtures may be appropriate in the context of themethods of the present invention, provided that the VEGF antagonist isnot inactivated by the formulation and the formulation isphysiologically compatible and tolerable with the route ofadministration. See also Powell et al. PDA (1998) J Pharm Sci Technol.52:238-311 and the citations therein for additional information relatedto excipients and carriers well known to pharmaceutical chemists.

Pharmaceutical formulations useful for administration by injection inthe context of the present invention may be prepared by dissolving,suspending or emulsifying a VEGF antagonist in a sterile aqueous mediumor an oily medium conventionally used for injections. As the aqueousmedium for injections, there are, for example, physiological saline, anisotonic solution containing glucose and other auxiliary agents, etc.,which may be used in combination with an appropriate solubilizing agentsuch as an alcohol (e.g., ethanol), a polyalcohol (e.g., propyleneglycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castoroil)], etc. As the oily medium, there may be employed, e.g., sesame oil,soybean oil, etc., which may be used in combination with a solubilizingagent such as benzyl benzoate, benzyl alcohol, etc. The injection thusprepared can be filled in an appropriate ampoule if desired.

Modes of Administration

The VEGF antagonist (or pharmaceutical formulation comprising the VEGFantagonist) may be administered to the patient by any known deliverysystem and/or administration method. In certain embodiments, the VEGFantagonist is administered to the patient by ocular, intraocular,intravitreal or subconjunctival injection. In other embodiments, theVEGF antagonist can be administered to the patient by topicaladministration, e.g., via eye drops or other liquid, gel, ointment orfluid which contains the VEGF antagonist and can be applied directly tothe eye. Other possible routes of administration include, e.g.,intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, and oral.

Amount of VEGF Antagonist Administered

Each dose of VEGF antagonist administered to the patient over the courseof the treatment regimen may contain the same, or substantially thesame, amount of VEGF antagonist. Alternatively, the quantity of VEGFantagonist contained within the individual doses may vary over thecourse of the treatment regimen. For example, in certain embodiments, afirst quantity of VEGF antagonist is administered in the initial dose, asecond quantity of VEGF antagonist is administered in the secondarydoses, and a third quantity of VEGF antagonist is administered in thetertiary doses. The present invention contemplates dosing schemes inwhich the quantity of VEGF antagonist contained within the individualdoses increases over time (e.g., each subsequent dose contains more VEGFantagonist than the last), decreases over time (e.g., each subsequentdose contains less VEGF antagonist than the last), initially increasesthen decreases, initially decreases then increases, or remains the samethroughout the course of the administration regimen.

The amount of VEGF antagonist administered to the patient in each doseis, in most cases, a therapeutically effective amount. As used herein,the phrase “therapeutically effective amount” means a dose of VEGFantagonist that results in a detectable improvement in one or moresymptoms or indicia of an angiogenic eye disorder, or a dose of VEGFantagonist that inhibits, prevents, lessens, or delays the progressionof an angiogenic eye disorder. In the case of an anti-VEGF antibody or aVEGF receptor-based chimeric molecule such as VEGFR1R2-FcΔC1(a), atherapeutically effective amount can be from about 0.05 mg to about 5mg, e.g., about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg,about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg,about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg,about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 1.0 mg,about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg,about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45 mg, about 1.5 mg,about 1.55 mg, about 1.6 mg, about 1.65 mg, about 1.7 mg, about 1.75 mg,about 1.8 mg, about 1.85 mg, about 1.9 mg, about 2.0 mg, about 2.05 mg,about 2.1 mg, about 2.15 mg, about 2.2 mg, about 2.25 mg, about 2.3 mg,about 2.35 mg, about 2.4 mg, about 2.45 mg, about 2.5 mg, about 2.55 mg,about 2.6 mg, about 2.65 mg, about 2.7 mg, about 2.75 mg, about 2.8 mg,about 2.85 mg, about 2.9 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg,about 4.5 mg, or about 5.0 mg of the antibody or receptor-based chimericmolecule.

The amount of VEGF antagonist contained within the individual doses maybe expressed in terms of milligrams of antibody per kilogram of patientbody weight (i.e., mg/kg). For example, the VEGF antagonist may beadministered to a patient at a dose of about 0.0001 to about 10 mg/kg ofpatient body weight.

Treatment Population and Efficacy

The methods of the present invention are useful for treating angiogeniceye disorders in patients that have been diagnosed with or are at riskof being afflicted with an angiogenic eye disorder. Generally, themethods of the present invention demonstrate efficacy within 104 weeksof the initiation of the treatment regimen (with the initial doseadministered at “week 0”), e.g., by the end of week 16, by the end ofweek 24, by the end of week 32, by the end of week 40, by the end ofweek 48, by the end of week 56, etc. In the context of methods fortreating angiogenic eye disorders such as AMD, CRVO, and DME, “efficacy”means that, from the initiation of treatment, the patient exhibits aloss of 15 or fewer letters on the Early Treatment Diabetic RetinopathyStudy (ETDRS) visual acuity chart. In certain embodiments, “efficacy”means a gain of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ormore) letters on the ETDRS chart from the time of initiation oftreatment.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the methods and compositions of the invention, and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to ensure accuracy with respect tonumbers used (e.g., amounts, temperature, etc.) but some experimentalerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, molecular weight is averagemolecular weight, temperature is in degrees Centigrade, and pressure isat or near atmospheric.

The exemplary VEGF antagonist used in all Examples set forth below is adimeric molecule having two functional VEGF binding units. Eachfunctional binding unit is comprised of Ig domain 2 from VEGFR1 fused toIg domain 3 from VEGFR2, which in turn is fused to the hinge region of ahuman IgG1 Fc domain (VEGFR1R2-FcΔC1(a); encoded by SEQ ID NO:1). ThisVEGF antagonist is referred to in the examples below as “VEGFT”. Forpurposes of the following Examples, “monthly” dosing is equivalent todosing once every four weeks.

Example 1: Phase I Clinical Trial of Intravitreally Administered VEGFReceptor-Based Chimeric Molecule (VEGFT) in Subjects with NeovascularAMD

In this Phase I study, 21 subjects with neovascular AMD received asingle intravitreal (IVT) dose of VEGFT. Five groups of three subjectseach received either 0.05, 0.15, 0.5, 2 or 4 mg of VEGFT, and a sixthgroup of six subjects received 1 mg. No serious adverse events relatedto the study drug, and no identifiable intraocular inflammation wasreported. Preliminary results showed that, following injection of VEGFT,a rapid decrease in foveal thickness and macular volume was observedthat was maintained through 6 weeks. At Day 43 across all dose groups,mean excess retinal thickness [excess retinal thickness=(retinalthickness−179μ)] on optical coherence tomography (OCT) was reduced from119μ to 27μ as assessed by Fast Macular Scan and from 194μ to 60μ asassessed using a single Posterior Pole scan. The mean increase in bestcorrected visual acuity (BCVA) was 4.75 letters, and BCVA was stable orimproved in 95% of subjects. In the 2 highest dose groups (2 and 4 mg),the mean increase in BCVA was 13.5 letters, with 3 of 6 subjectsdemonstrating improvement of 3 lines.

Example 2: Phase II Clinical Trial of Repeated Doses of IntravitreallyAdministered VEGF Receptor-Based Chimeric Molecule (VEGFT) in Subjectswith Neovascular AMD

This study was a double-masked, randomized study of 3 doses (0.5, 2, and4 mg) of VEGFT tested at 4-week and/or 12-week dosing intervals. Therewere 5 treatment arms in this study, as follows: 1) 0.5 mg every 4weeks, 2) 0.5 mg every 12 weeks, 3) 2 mg every 4 weeks, 4) 2 mg every 12weeks and 5) 4 mg every 12 weeks. Subjects were dosed at a fixedinterval for the first 12 weeks, after which they were evaluated every 4weeks for 9 months, during which additional doses were administeredbased on pre-specified criteria. All subjects were then followed for oneyear after their last dose of VEGFT. Preliminary data from a pre-plannedinterim analysis indicated that VEGFT met its primary endpoint of astatistically significant reduction in retinal thickness after 12 weekscompared with baseline (all groups combined, decrease of 135μ,p<0.0001). Mean change from baseline in visual acuity, a key secondaryendpoint of the study, also demonstrated statistically significantimprovement (all groups combined, increase of 5.9 letters, p<0.0001).Moreover, patients in the dose groups that received only a single dose,on average, demonstrated a decrease in excess retinal thickness(p<0.0001) and an increase in visual acuity (p=0.012) at 12 weeks. Therewere no drug-related serious adverse events, and treatment with the VEGFantagonists was generally well-tolerated. The most common adverse eventswere those typically associated with intravitreal injections.

Example 3: Phase I Clinical Trial of Systemically Administered VEGFReceptor-Based Chimeric Molecule (VEGFT) in Subjects with NeovascularAMD

This study was a placebo-controlled, sequential-group, dose-escalatingsafety, tolerability and bioeffect study of VEGFT by IV infusion insubjects with neovascular AMD. Groups of 8 subjects meeting eligibilitycriteria for subfoveal choroidal neovascularization (CNV) related to AMDwere assigned to receive 4 IV injections of VEGFT or placebo at doselevels of 0.3, 1, or 3 mg/kg over an 8-week period.

Most adverse events that were attributed to VEGFT were mild to moderatein severity, but 2 of 5 subjects treated with 3 mg/kg experienceddose-limiting toxicity (DLT) (one with Grade 4 hypertension and one withGrade 2 proteinuria); therefore, all subjects in the 3 mg/kg dose groupdid not enter the study. The mean percent changes in excess retinalthickness were: −12%, −10%, −66%, and −60% for the placebo, 0.3, 1, and3 mg/kg dose groups at day 15 (ANOVA p<0.02), and −5.6%, +47.1%, and−63.3% for the placebo, 0.3, and 1 mg/kg dose groups at day 71 (ANOVAp<0.02). There was a numerical improvement in BCVA in the subjectstreated with VEGFT. As would be expected in such a small study, theresults were not statistically significant.

Example 4: Phase III Clinical Trials of the Efficacy, Safety, andTolerability of Repeated Doses of Intravitreal VEGFT in Subjects withNeovascular Age-Related Macular Degeneration A. Objectives, Hypothesesand Endpoints

Two parallel Phase III clinical trials were carried out to investigatethe use of VEGFT to treat patients with the neovascular form ofage-related macular degeneration (Study 1 and Study 2). The primaryobjective of these studies was to assess the efficacy of IVTadministered VEGFT compared to ranibizumab (Lucentis®, Genentech, Inc.),in a non-inferiority paradigm, in preventing moderate vision loss insubjects with all subtypes of neovascular AMD.

The secondary objectives were (a) to assess the safety and tolerabilityof repeated IVT administration of VEGFT in subjects with all sub-typesof neovascular AMD for periods up to 2 years; and (b) to assess theeffect of repeated IVT administration of VEGFT on Vision-Related Qualityof Life (QOL) in subjects with all sub-types of neovascular AMD.

The primary hypothesis of these studies was that the proportion ofsubjects treated with VEGFT with stable or improved BCVA (<15 letterslost) is similar to the proportion treated with ranibizumab who havestable or improved BCVA, thereby demonstrating non-inferiority.

The primary endpoint for these studies was the prevention of vision lossof greater than or equal to 15 letters on the ETDRS chart, compared tobaseline, at 52 weeks. Secondary endpoints were as follows: (a) changefrom baseline to Week 52 in letter score on the ETDRS chart; (b) gainfrom baseline to Week 52 of 15 letters or more on the ETDRS chart; (c)change from baseline to Week 52 in total NEI VFQ-25 score; and (d)change from baseline to Week 52 in CNV area.

B. Study Design

For each study, subjects were randomly assigned in a 1:1:1:1 ratio to 1of 4 dosing regimens: (1) 2 mg VEGFT administered every 4 weeks (2Q4);(2) 0.5 mg VEGFT administered every 4 weeks (0.5Q4); (3) 2 mg VEGFTadministered every 4 weeks to week 8 and then every 8 weeks (with shaminjection at the interim 4-week visits when study drug was notadministered (2Q8); and (4) 0.5 mg ranibizumab administered every 4weeks (RQ4). Subjects assigned to (2Q8) received the 2 mg injectionevery 4 weeks to week 8 and then a sham injection at interim 4-weekvisits (when study drug is not to be administered) during the first 52weeks of the studies. (No sham injection were given at Week 52).

The study duration for each subject was scheduled to be 96 weeks plusthe recruitment period. For the first 52 weeks (Year 1), subjectsreceived an IVT or sham injection in the study eye every 4 weeks. (Nosham injections were given at Week 52). During the second year of thestudy, subjects will be evaluated every 4 weeks and will receive IVTinjection of study drug at intervals determined by specific dosingcriteria, but at least every 12 weeks. (During the second year of thestudy, sham injections will not be given.) During this period,injections may be given as frequently as every 4 weeks, but no lessfrequently than every 12 weeks, according to the following criteria: (i)increase in central retinal thickness of ≥100 μm compared to the lowestprevious value as measured by optical coherence tomography (OCT); or(ii) a loss from the best previous letter score of at least 5 ETDRSletters in conjunction with recurrent fluid as indicated by OCT; or(iii) new or persistent fluid as indicated by OCT; or (iv) new onsetclassic neovascularization, or new or persistent leak on fluoresceinangiography (FA); or (v) new macular hemorrhage; or (vi) 12 weeks haveelapsed since the previous injection. According to the present protocol,subjects must receive an injection at least every 12 weeks.

Subjects were evaluated at 4 weeks intervals for safety and bestcorrected visual acuity (BCVA) using the 4 meter ETDRS protocol. Qualityof Life (QOL) was evaluated using the NEI VFQ-25 questionnaire. OCT andFA examinations were conducted periodically.

Approximately 1200 subjects were enrolled, with a target enrollment of300 subjects per treatment arm.

To be eligible for this study, subjects were required to have subfovealchoroidal neovascularization (CNV) secondary to AMD. “Subfoveal” CNV wasdefined as the presence of subfoveal neovascularization, documented byFA, or presence of a lesion that is juxtafoveal in locationangiographically but affects the fovea. Subject eligibility wasconfirmed based on angiographic criteria prior to randomization.

Only one eye was designated as the study eye. For subjects who meteligibility criteria in both eyes, the eye with the worse VA wasselected as the study eye. If both eyes had equal VA, the eye with theclearest lens and ocular media and least amount of subfoveal scar orgeographic atrophy was selected. If there was no objective basis forselecting the study eye, factors such as ocular dominance, other ocularpathology and subject preference were considered in making theselection.

Inclusion criteria for both studies were as follows: (i) signed Informedconsent; (ii) at least 50 years of age; (iii) active primary subfovealCNV lesions secondary to AMD, including juxtafoveal lesions that affectthe fovea as evidenced by FA in the study eye; (iv) CNV at least 50% oftotal lesion size; (v) early treatment diabetic retinopathy study(ETDRS) best-corrected visual acuity of: 20/40 to 20/320 (letter scoreof 73 to 25) in the study eye; (vi) willing, committed, and able toreturn for all clinic visits and complete all study-related procedures;and (vii) able to read, understand and willing to sign the informedconsent form (or, if unable to read due to visual impairment, be read toverbatim by the person administering the informed consent or a familymember).

Exclusion criteria for both studies were as follows: 1. Any prior ocular(in the study eye) or systemic treatment or surgery for neovascular AMDexcept dietary supplements or vitamins. 2. Any prior or concomitanttherapy with another investigational agent to treat neovascular AMD inthe study eye, except dietary supplements or vitamins. 3. Priortreatment with anti-VEGF agents as follows: (a) Prior treatment withanti-VEGF therapy in the study eye was not allowed; (b) Prior treatmentwith anti-VEGF therapy in the fellow eye with an investigational agent(not FDA approved, e.g. bevacizumab) was allowed up to 3 months prior tofirst dose in the study, and such treatments were not allowed during thestudy. Prior treatment with an approved anti-VEGF therapy in the felloweye was allowed; (c) Prior systemic anti-VEGF therapy, investigationalor FDA/Health Canada approved, was only allowed up to 3 months prior tofirst dose, and was not allowed during the study. 4. Total lesionsize >12 disc areas (30.5 mm2, including blood, scars andneovascularization) as assessed by FA in the study eye. 5. Subretinalhemorrhage that is either 50% or more of the total lesion area, or ifthe blood is under the fovea and is 1 or more disc areas in size in thestudy eye. (If the blood is under the fovea, then the fovea must besurrounded 270 degrees by visible CNV.) 6. Scar or fibrosis, makingup >50% of total lesion in the study eye. 7. Scar, fibrosis, or atrophyinvolving the center of the fovea. 8. Presence of retinal pigmentepithelial tears or rips involving the macula in the study eye. 9.History of any vitreous hemorrhage within 4 weeks prior to Visit 1 inthe study eye. 10. Presence of other causes of CNV, including pathologicmyopia (spherical equivalent of −8 diopters or more negative, or axiallength of 25 mm or more), ocular histoplasmosis syndrome, angioidstreaks, choroidal rupture, or multifocal choroiditis in the study eye.11. History or clinical evidence of diabetic retinopathy, diabeticmacular edema or any other vascular disease affecting the retina, otherthan AMD, in either eye. 12. Prior vitrectomy in the study eye. 13.History of retinal detachment or treatment or surgery for retinaldetachment in the study eye. 14. Any history of macular hole of stage 2and above in the study eye. 15. Any intraocular or periocular surgerywithin 3 months of Day 1 on the study eye, except lid surgery, which maynot have taken place within 1 month of day 1, as long as it was unlikelyto interfere with the injection. 16. Prior trabeculectomy or otherfiltration surgery in the study eye. 17. Uncontrolled glaucoma (definedas intraocular pressure greater than or equal to 25 mm Hg despitetreatment with anti-glaucoma medication) in the study eye. 18. Activeintraocular inflammation in either eye. 19. Active ocular or periocularinfection in either eye. 20. Any ocular or periocular infection withinthe last 2 weeks prior to Screening in either eye. 21. Any history ofuveitis in either eye. 22. Active scleritis or episcleritis in eithereye. 23. Presence or history of scleromalacia in either eye. 24. Aphakiaor pseudophakia with absence of posterior capsule (unless it occurred asa result of a yttrium aluminum garnet [YAG] posterior capsulotomy) inthe study eye. 25. Previous therapeutic radiation in the region of thestudy eye. 26. History of corneal transplant or corneal dystrophy in thestudy eye. 27. Significant media opacities, including cataract, in thestudy eye which might interfere with visual acuity, assessment ofsafety, or fundus photography. 28. Any concurrent intraocular conditionin the study eye (e.g. cataract) that, in the opinion of theinvestigator, could require either medical or surgical interventionduring the 96 week study period. 29. Any concurrent ocular condition inthe study eye which, in the opinion of the investigator, could eitherincrease the risk to the subject beyond what is to be expected fromstandard procedures of intraocular injection, or which otherwise mayinterfere with the injection procedure or with evaluation of efficacy orsafety. 30. History of other disease, metabolic dysfunction, physicalexamination finding, or clinical laboratory finding giving reasonablesuspicion of a disease or condition that contraindicates the use of aninvestigational drug or that might affect interpretation of the resultsof the study or render the subject at high risk for treatmentcomplications. 31. Participation as a subject in any clinical studywithin the 12 weeks prior to Day 1. 32. Any systemic or ocular treatmentwith an investigational agent in the past 3 months prior to Day 1. 33.The use of long acting steroids, either systemically or intraocularly,in the 6 months prior to day 1. 34. Any history of allergy to povidoneiodine. 35. Known serious allergy to the fluorescein sodium forinjection in angiography. 36. Presence of any contraindicationsindicated in the FDA Approved label for ranibizumab (Lucentis®). 37.Females who were pregnant, breastfeeding, or of childbearing potential,unwilling to practice adequate contraception throughout the study.Adequate contraceptive measures include oral contraceptives (stable usefor 2 or more cycles prior to screening); IUD; Depo-Provera®; Norplant®System implants; bilateral tubal ligation; vasectomy; condom ordiaphragm plus either contraceptive sponge, foam or jelly.

Subjects were not allowed to receive any standard or investigationalagents for treatment of their AMD in the study eye other than theirassigned study treatment with VEGFT or ranibizumab as specified in theprotocol until they completed the Completion/Early Termination visitassessments. This includes medications administered locally (e.g., IVT,topical, juxtascleral or periorbital routes), as well as thoseadministered systemically with the intent of treating the study and/orfellow eye.

The study procedures are summarized as follows:

Best Corrected Visual Acuity:

Visual function of the study eye and the fellow eye were assessed usingthe ETDRS protocol (The Early Treatment Diabetic Retinopathy StudyGroup) at 4 meters. Visual Acuity examiners were certified to ensureconsistent measurement of BCVA. The VA examiners were required to remainmasked to treatment assignment.

Optical Coherence Tomography:

Retinal and lesion characteristics were evaluated using OCT on the studyeye. At the Screen Visit (Visit 1) images were captured and transmittedfor both eyes. All OCT images were captured using the Zeiss Stratus OCT™with software Version 3 or greater. OCT images were sent to anindependent reading center where images were read by masked readers atvisits where OCTs were required. All OCTs were electronically archivedat the site as part of the source documentation. A subset of OCT imageswere read. OCT technicians were required to be certified by the readingcenter to ensure consistency and quality in image acquisition. Adequateefforts were made to ensure that OCT technicians at the site remainedmasked to treatment assignment.

Fundus Photography and Fluorescein Angiography (FA):

The anatomical state of the retinal vasculature of the study eye wasevaluated by funduscopic examination, fundus photography and FA. At theScreen Visit (Visit 1) funduscopic examination, fundus photography andFA were captured and transmitted for both eyes. Fundus and angiographicimages were sent to an independent reading center where images were readby masked readers. The reading center confirmed subject eligibilitybased on angiographic criteria prior to randomization. All FAs andfundus photographs were archived at the site as part of the sourcedocumentation. Photographers were required to be certified by thereading center to ensure consistency and quality in image acquisition.Adequate efforts were made to ensure that all photographers at the siteremain masked to treatment assignment.

Vision-Related Quality of Life:

Vision-related QOL was assessed using the National Eye Institute 25-ItemVisual Function Questionnaire (NEI VFQ-25) in theinterviewer-administered format. NEI VFQ-25 was administered bycertified personnel at a contracted call center. At the screening visit,the sites assisted the subject and initiated the first call to the callcenter to collect all of the subject's contact information and tocomplete the first NEI VFQ-25 on the phone prior to randomization andIVT injection. For all subsequent visits, the call center called thesubject on the phone, prior to IVT injection, to complete thequestionnaire.

Intraocular Pressure:

Intraocular pressure (IOP) of the study eye was measured usingapplanation tonometry or Tonopen. The same method of IOP measurement wasused in each subject throughout the study.

C. Results Summary (52 Week Data)

The primary endpoint (prevention of moderate or severe vision loss asdefined above) was met for all three VEGFT groups (2Q4, 0.5Q4 and 2Q8)in this study. The results from both studies are summarized in Table 1.

TABLE 1 Ranibizumab VEGFT VEGFT VEGFT 0.5 mg 0.5 mg 2 mg 2 mg monthlymonthly monthly every 8 (RQ4) (0.5Q4) (2Q4) weeks^([a]) (2Q8)Maintenance of vision* (% patients losing <15 letters) at week 52 versusbaseline Study 1 94.4% 95.9%** 95.1%** 95.1%** Study 2 94.4% 96.3%**95.6%** 95.6%** Mean improvement in vision* (letters) at 52 weeks versusbaseline (p-value vs RQ4)*** Study 1 8.1 6.9 (NS) 10.9 (p < 0.01) 7.9(NS) Study 2 9.4 9.7 (NS) 7.6 (NS) 8.9 (NS  ^([a])Following threeinitial monthly doses *Visual acuity was measured as the total number ofletters read correctly on the Early Treatment Diabetic Retinopathy Study(ETDRS) eye chart. **Statistically non-inferior based on anon-inferiority margin of 10%, using confidence interval approach (95.1%and 95% for Study 1 and Study 2, respectively) ***Test for superiorityNS = non-significant

In Study 1, patients receiving VEGFT 2 mg monthly (2Q4) achieved astatistically significant greater mean improvement in visual acuity atweek 52 versus baseline (secondary endpoint), compared to ranibizumab0.5 mg monthly (RQ4); patients receiving VEGFT 2 mg monthly on averagegained 10.9 letters, compared to a mean 8.1 letter gain with ranibizumab0.5 mg dosed every month (p<0.01). All other dose groups of VEGFT inStudy 1 and all dose groups in Study 2 were not statistically differentfrom ranibizumab in this secondary endpoint.

A generally favorable safety profile was observed for both VEGFT andranibizumab. The incidence of ocular treatment emergent adverse eventswas balanced across all four treatment groups in both studies, with themost frequent events associated with the injection procedure, theunderlying disease, and/or the aging process. The most frequent ocularadverse events were conjunctival hemorrhage, macular degeneration, eyepain, retinal hemorrhage, and vitreous floaters. The most frequentserious non-ocular adverse events were typical of those reported in thiselderly population who receive intravitreal treatment for wet AMD; themost frequently reported events were falls, pneumonia, myocardialinfarction, atrial fibrillation, breast cancer, and acute coronarysyndrome. There were no notable differences among the study arms.

Example 5: Phase II Clinical Trial of VEGFT in Subjects with DiabeticMacular Edema (DME)

In this study, 221 patients with clinically significant DME with centralmacular involvement were randomized, and 219 patients were treated withbalanced distribution over five groups. The control group receivedmacular laser therapy at baseline, and patients were eligible for repeatlaser treatments, but no more frequently than at 16 week intervals. Theremaining four groups received VEGFT by intravitreal injection asfollows: Two groups received 0.5 or 2 mg of VEGFT once every four weeksthroughout the 12-month dosing period (0.5Q4 and 2Q4, respectively). Twogroups received three initial doses of 2 mg VEGFT once every four weeks(i.e., at baseline, and weeks 4 and 8), followed through week 52 byeither once every 8 weeks dosing (2Q8) or as needed dosing with verystrict repeat dosing criteria (PRN). Mean gains in visual acuity versusbaseline were as shown in Table 2:

TABLE 2 Mean change in Mean change in visual acuity visual acuity atweek 24 at week 52 versus baseline versus baseline n (letters) (letters)Laser 44 2.5 −1.3 VEGFT 0.5 mg 44 8.6** 11.0** monthly (0.5Q4) VEGFT 2mg monthly 44 11.4** 13.1** (2Q4) VEGFT 2 mg every 8 42 8.5** 9.7**weeks^([a]) (2Q8) VEGFT 2 mg as 45 10.3** 12.0** needed^([a]) (PRN)^([a])Following three initial monthly doses **p < 0.01 versus laser

In this study, the visual acuity gains achieved with VEGFTadministration at week 24 were maintained or numerically improved up tocompletion of the study at week 52 in all VEGFT study groups, including2 mg dosed every other month

As demonstrated in the foregoing Examples, the administration of VEGFTto patients suffering from angiogenic eye disorders (e.g., AMD and DME)at a frequency of once every 8 weeks, following a single initial doseand two secondary doses administered four weeks apart, resulted insignificant prevention of moderate or severe vision loss or improvementsin visual acuity.

Example 6: A Randomized, Multicenter, Double-Masked Trial in TreatmentNaïve Patients with Macular Edema Secondary to CRVO

In this randomized, double-masked, Phase 3 study, patients received 6monthly injections of either 2 mg intravitreal VEGFT (114 patients) orsham injections (73 patients). From Week 24 to Week 52, all patientsreceived 2 mg VEGFT as-needed (PRN) according to retreatment criteria.Thus, “sham-treated patients” means patients who received shaminjections once every four weeks from Week 0 through Week 20, followedby intravitreal VEGFT as needed from Week 24 through Week 52.“VEGFT-treated patients” means patients who received VEGFT intravitrealinjections once every four weeks from Week 0 through Week 20, followedby intravitreal VEGFT as needed from Week 24 through Week 52. Theprimary endpoint was the proportion of patients who gained ≥15 ETDRSletters from baseline at Week 24. Secondary visual, anatomic, andQuality of Life NEI VFQ-25 outcomes at Weeks 24 and 52 were alsoevaluated.

At Week 24, 56.1% of VEGFT-treated patients gained ≥15 ETDRS lettersfrom baseline vs 12.3% of sham-treated patients (P<0.0001). Similarly,at Week 52, 55.3% of VEGFT-treated patients gained ≥15 letters vs 30.1%of sham-treated patients (P<0.01). At Week 52, VEGFT-treated patientsgained a mean of 16.2 letters vs 3.8 letters for sham-treated patients(P<0.001). Mean number of injections was 2.7 for VEGFT-treated patientsvs 3.9 for sham-treated patients. Mean change in central retinalthickness was −413.0 μm for VEGFT-treated patients vs −381.8 μm forsham-treated patients. The proportion of patients with ocularneovascularization at Week 24 were 0% for VEGFT-treated patients and6.8% for sham-treated patients, respectively; at Week 52 after receivingVEGFT PRN, proportions were 0% and 6.8% for VEGFT-treated andsham-treated. At Week 24, the mean change from baseline in the VFQ-25total score was 7.2 vs 0.7 for the VEGFT-treated and sham-treatedgroups; at Week 52, the scores were 7.5 vs 5.1 for the VEGFT-treated andsham-treated groups.

This Example confirms that dosing monthly with 2 mg intravitreal VEGFTinjection resulted in a statistically significant improvement in visualacuity at Week 24 that was maintained through Week 52 with PRN dosingcompared with sham PRN treatment. VEGFT was generally well tolerated andhad a generally favorable safety profile.

Example 7: Dosing Regimens

Specific, non-limiting examples of dosing regimens within the scope ofthe present invention are as follows:

VEGFT 2 mg (0.05 mL) administered by intravitreal injection once every 4weeks (monthly).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 8 weeks, followed by 2 mg (0.05 mL) via intravitrealinjection once every 8 weeks.

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 8 weeks, followed by 2 mg (0.05 mL) via intravitrealinjection on a less frequent basis based on visual and/or anatomicaloutcomes (as assessed by a physician or other qualified medicalprofessional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 8 weeks, followed by 2 mg (0.05 mL) via intravitrealinjection administered pro re nata (PRN) based on visual and/oranatomical outcomes (as assessed by a physician or other qualifiedmedical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 12 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection once every 8 weeks.

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 12 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection on a less frequent basis based on visual and/oranatomical outcomes (as assessed by a physician or other qualifiedmedical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 12 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection administered pro re nata (PRN) based on visualand/or anatomical outcomes (as assessed by a physician or otherqualified medical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 16 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection once every 8 weeks.

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 16 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection on a less frequent basis based on visual and/oranatomical outcomes (as assessed by a physician or other qualifiedmedical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 16 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection administered pro re nata (PRN) based on visualand/or anatomical outcomes (as assessed by a physician or otherqualified medical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 20 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection once every 8 weeks.

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 20 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection on a less frequent basis based on visual and/oranatomical outcomes (as assessed by a physician or other qualifiedmedical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 20 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection administered pro re nata (PRN) based on visualand/or anatomical outcomes (as assessed by a physician or otherqualified medical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 24 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection once every 8 weeks.

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 24 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection on a less frequent basis based on visual and/oranatomical outcomes (as assessed by a physician or other qualifiedmedical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 24 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection administered pro re nata (PRN) based on visualand/or anatomical outcomes (as assessed by a physician or otherqualified medical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 28 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection once every 8 weeks.

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 28 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection on a less frequent basis based on visual and/oranatomical outcomes (as assessed by a physician or other qualifiedmedical professional).

VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4weeks for the first 28 weeks, followed by 2 mg (0.05 mL) viaintravitreal injection administered pro re nata (PRN) based on visualand/or anatomical outcomes (as assessed by a physician or otherqualified medical professional).

VEGFT 2 mg (0.05 mL) administered by intravitreal injection as a singleinitial dose, followed by additional doses administered pro re nata(PRN) based on visual and/or anatomical outcomes (as assessed by aphysician or other qualified medical professional).

Variations on the above-described dosing regimens would be appreciatedby persons of ordinary skill in the art and are also within the scope ofthe present invention. For example, the amount of VEGFT and/or volume offormulation administered to a patient may be varied based on patientcharacteristics, severity of disease, and other diagnostic assessmentsby a physician or other qualified medical professional.

Any of the foregoing administration regimens may be used for thetreatment of, e.g., age-related macular degeneration (e.g., wet AMD,exudative AMD, etc.), retinal vein occlusion (RVO), central retinal veinocclusion (CRVO; e.g., macular edema following CRVO), branch retinalvein occlusion (BRVO), diabetic macular edema (DME), choroidalneovascularization (CNV; e.g., myopic CNV), iris neovascularization,neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferativevitreoretinopathy (PVR), optic disc neovascularization, cornealneovascularization, retinal neovascularization, vitrealneovascularization, pannus, pterygium, vascular retinopathy, etc.

Sequences

SEQ ID NO: 1 (DNA sequence having 1377 nucleo- tides):ATGGTCAGCTACTGGGACACCGGGGTCCTGCTGTGCGCGCTGCTCAGCTGTCTGCTTCTCACAGGATCTAGTTCCGGAAGTGATACCGGTAGACCTTTCGTAGAGATGTACAGTGAAATCCCCGAAATTATACACATGACTGAAGGAAGGGAGCTCGTCATTCCCTGCCGGGTTACGTCACCTAACATCACTGTTACTTTAAAAAAGTTTCCACTTGACACTTTGATCCCTGATGGAAAACGCATAATCTGGGACAGTAGAAAGGGCTTCATCATATCAAATGCAACGTACAAAGAAATAGGGCTTCTGACCTGTGAAGCAACAGTCAATGGGCATTTGTATAAGACAAACTATCTCACACATCGACAAACCAATACAATCATAGATGTGGTTCTGAGTCCGTCTCATGGAATTGAACTATCTGTTGGAGAAAAGCTTGTCTTAAATTGTACAGCAAGAACTGAACTAAATGTGGGGATTGACTTCAACTGGGAATACCCTTCTTCGAAGCATCAGCATAAGAAACTTGTAAACCGAGACCTAAAAACCCAGTCTGGGAGTGAGATGAAGAAATTTTTGAGCACCTTAACTATAGATGGTGTAACCCGGAGTGACCAAGGATTGTACACCTGTGCAGCATCCAGTGGGCTGATGACCAAGAAGAACAGCACATTTGTCAGGGTCCATGAAAAGGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGASEQ ID NO: 2 (polypeptide sequence haying 458 amino acids):MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLICEATVNGHLYKTNYLTHRQINTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

1.-20. (canceled)
 21. A method for treating macular edema followingretinal vein occlusion in a human subject comprising administering 2 mgaflibercept to the subject by intravitreal injection once every 4 weeks.22. The method of claim 21 wherein the aflibercept is administered in avolume of 0.05 ml.
 23. The method of claim 22 wherein the aflibercept isin a pharmaceutical formulation comprising a pharmaceutically acceptablecarrier.